The function of human regulatory regions depends exquisitely on their local genomic environment and on cellular context, complicating experimental analysis of common disease- and trait-associated variants that localize within regulatory DNA. We use allelically resolved genomic DNase I footprinting data encompassing 166 individuals and 114 cell types to identify >60,000 common variants that directly influence transcription factor occupancy and regulatory DNA accessibility in vivo. The unprecedented scale of these data enables systematic analysis of the impact of sequence variation on transcription factor occupancy in vivo. We leverage this analysis to develop accurate models of variation affecting the recognition sites for diverse transcription factors and apply these models to discriminate nearly 500,000 common regulatory variants likely to affect transcription factor occupancy across the human genome. The approach and results provide a new foundation for the analysis and interpretation of noncoding variation in complete human genomes and for systems-level investigation of disease-associated variants.
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This work was supported by US National Institutes of Health grants U54HG004592, U54HG007010, U01ES01156, 1S10RR026770 and 1S10OD017999 to J.A.S. and National Institute of Mental Health fellowship F31MH094073 to M.T.M. J.V. was supported by a National Science Foundation Graduate Research Fellowship under grant DGE-071824.
The authors declare no competing financial interests.
Supplementary Figures 1–13 and Supplementary Tables 3–13 and 15–17. (PDF 11308 kb)
DNase I mapping of 116 cell types and tissues used in the study, including the shorthand name for the tissue. Signal portion of tags (SPOT) scores are a measure of enrichment and refer to the proportion of reads mapping within a DHS. Read counts include reads mapped uniquely with ≤2 mismatches to an autosomal chromosome; paired-end reads were required to both properly map to the same chromosome. Read counts are in millions. *, FL_E was excluded from the primary analysis and used for independent validation of the predictions in Figure 7. Previously published data sets are labeled by publication (refs. 2,3,24,27,64–67). (TXT 35 kb)
ChIP-seq mapping of CTCF and H3K4me3 in 77 cell types and tissues used in the study, Signal portion of tags (SPOT) scores are a measure of enrichment and refer to the proportion of reads mapping within a DHS. Read counts include reads mapped uniquely with ≤2 mismatches to an autosomal chromosome; paired-end reads were required to both properly map to the same chromosome. Read counts are in millions. Previously published data sets are labeled by publication (refs. 2,17,44,68). (TXT 12 kb)
Clustering of motifs from the JASPAR, UniProbe, TRANSFAC and Jolma et al.35 databases. Each TF cluster is listed along with the names of constituent motifs. (TXT 34 kb)
SNPs are listed by their hg19 coordinates. The rsID is used for SNPs in dbSNP 138. SNPs are classified as imbalanced as in Figure 1c. PctRef refers to the proportion of reads mapping to the reference allele (Fig.1d). (TXT 27676 kb)
Motif weblogos from the JASPAR, UniPROBE and Jolma et al.35 databases grouped by TF cluster. Motifs from TRANSFAC are listed by name without showing a weblogo. (PDF 23365 kb)
List of SNVs from dbSNP 138 overlapping a TF recognition sequence in a DHS hotspot predicted to affect accessibility with a score greater than 0.10. The file is in extended bed format using hg19 coordinates and includes a header line. Each row contains the SNP coordinates and dbSNP ID, a score scaled as the probability of imbalance, the PWM name and strand, the position of the SNP relative to the PWM match and the two alleles of the SNP. (ZIP 9362 kb)
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Maurano, M., Haugen, E., Sandstrom, R. et al. Large-scale identification of sequence variants influencing human transcription factor occupancy in vivo. Nat Genet 47, 1393–1401 (2015). https://doi.org/10.1038/ng.3432
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